Hydroisoindoline tachykinin receptor antagonists

Abstract

The present invention is directed to certain hydroisoindoline compounds of formula I which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

1. A method for treating alcohol dependence in a patient in need thereof,
 comprising administering to the patient a therapeutically effective amount of a compound of formula I: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1 is selected from the group consisting of:
 (1) hydrogen, 
 (2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, 
 (3) cyclopentenone, which is unsubstituted or substituted with hydroxyl or methyl, 
 (4) —(CO)—C 1-6 alkyl, 
 (5) —(CO)—NH 2 , 
 (6) —(CO)—NHC 1-6 alkyl, and 
 (7) —(CO)—N(C 1-6 alkyl)(C 1-6 alkyl); 
 
 X is independently selected from the group consisting of:
 (1) hydrogen, 
 (2) fluorine, and 
 (3) methyl; 
 
 
       and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof. 
     
     
       2. The method according to  claim 1  wherein the compound of Formula I is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
       3. A method for treating alcohol dependence in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound which is